Rheumatoid arthritis (RA) is associated with the Dw4 subtype of HLA DR4. The molecular basis for this association is thought to be the amino acid sequence QKRAA in the third hypervariable region of the Dw4 b1 chain. How this shared epitope alters RA susceptibility or outcome is not known. Our preliminary experiments have shown (i) that the QKRAA sequence is expressed on major antigens from two human pathogens, the Epstein-Barr virus (EBV) gp110 protein and the E.coli dnaJ protein; (ii) that antibodies against the dnaJ protein cross-react with HLA Dw4 beta1 chains; (iii) that T cells reactive with the shared epitope are present in many normal adult humans that do not type as HLA Dw4; and (iv) that mice are tolerant to self MHC peptides that are homologous to the RA shared epitope. Based upon the data, we have postulated that the QKRAA sequence in HLA DR4 increases susceptibility to RA because it impairs immune regulation of E.coli and EBV infections, and/or promotes the emergence of cross-reactive T cells that can trigger autoimmunity. The proposed experiments will test this hypothesis by analyzing the fine specificity and magnitude of immune responses to dnaJ and gp110 in RA patients and normal subjects who do or do not express the QKRAA disease susceptibility epitope. The experiments will utilize as antigens wild type and mutant recombinant dnaJ and gp110 proteins, and synthetic peptides corresponding to different regions of the molecules. The responding cells and sera will come from both monozygotic and dizygotic RA twins, who are concordant or discordant or discordant for disease, and from patients with recent onset RA. The data collected in these experiments should provide fundamental information concerning how a short HLA DR hypervariable region peptide can change immune responses to two ubiquitous human pathogens, and thereby affect RA incidence or severity.